Organolithium reagents are used in both academic and industrial laboratories to carry out complex syntheses of medicinally important compounds. The underlying solvent- dependent aggregates and mechanisms of reaction are as complex as in any sub discipline in organometallic chemistry. We are the only group in the world with expertise in synthetic organic, organometallic, physical organic, analytical, and computational chemistry together in a single laboratory to produce fully integrated studies of structure, mechanism, and selectivity. In this proposal, we continue studies of the chemistry of lithium dialkylamides used prominently as the base of choice for difficult metalations central to many C-C bond forming processes. The program is fully integrated starting from a synthetic goal, observation, or question. Through a combination of structural and mechanistic studies we answer key questions or offer solutions to key problems. In this proposal we will focus on several pressing topics including: (1) We will complete studies of lithium diisopropylamide (LDA)-mediated metalations that all occur under the synthetically prominent conditions (THF at -78 oC) in which, ironically, complexity reaches a zenith because the aggregate-aggregate exchanges are not at equilibrium. (2) Related studies will focus on poorly understood LDA-LiX mixed aggregation effects observed under equilibrium conditions. (3) A collaboration starting with Amgen and expanding to include Zakarian (UCSB) will explore the structural and mechanistic basis of highly enantioselective reactions using a chiral dilithiated tetraamine. (4) Asymmetric C-N bond formation via 1,4-additions will be examined from a number of angles, all founded on previous studies in our lab. (5) The most overlooked of the three most prominent lithium amides-lithium tetramethylpiperdide-will be studied with the goal of expanding our understanding of how it metalates as well as developing pharmaceutically important hydrocarbon-soluble analogs. (6) Studies in collaboration with Paul Knochel of the rapidly developing class of tetramethylpiperidides based on magnesium and zinc will be examined. Overall, the work described in 6 aims promises to expand our most basic understanding of lithium amide structure-reactivity relationships and develop methods for use in organic synthesis.